In the international patent application WO9837894 the combination of phosphodiesterase inhibitors with adenylate cyclase agonists or guanylate cyclase agonists is disclosed for the treatment of inter alia pulmonary hypertension. In the international patent application WO9509636 a method for treating pulmonary hypertension is disclosed which comprises administering endotracheally or endobronchially to a subject an effective amount of a drug selected from the group consisting of cyclic nucleotides, phosphodiesterase inhibitors, nitric oxide precursors, nitric oxide donors and nitric oxide analogs, thereby decreasing pulmonary vascular resistance. In Cardiovasc. Rev & Rep 2002; 23, pp 274-279 Martin R. Wilkins et al review the use of phosphodiesterase inhibitors in the treatment of pulmonary hypertension. In Am J Physiol Lung Cell Mol Physiol 288: L103-L115, 2005 it is described that cAMP phosphodiesterase inhibitors potentiate effects of prostacyclin analogs in hypoxic pulmonary vascular remodelling. In Current Opinion in Investigational Drugs 2005 6(3), pp 283-288 Wang D et al describe novel approaches to use PDE4 inhibitors for antihypertensive therapy. In Current Opinion in Investigational Drugs 2002 3(8) Reid P describes that Roflumilast is metabolized in vivo to Roflumilast-N-oxide and that the both compounds behave in a similar manner in most test conditions. In the international patent application WO03070279 oral dosage forms containing a PDE4 inhibitor—exemplified exclusively by compositions comprising Roflumilast—for the treatment and prevention of all diseases regarded as treatable or preventable through the use of PDE4 inhibitors, including COPD are disclosed.
Pulmonary hypertension (PH) is defined by a mean pulmonary artery pressure (PAP) >25 mm Hg at rest or >30 mg Hg with exercise. According to current guidelines on diagnosis and treatment of pulmonary hypertension released by the European Society of Cardiology in 2004 (Eur Heart J 25: 2243-2278; 2004) clinical forms of PH are classified as (1) pulmonary arterial hypertension (PAH), (2) PH associated with left heart diseases, (3) PH associated with lung respiratory diseases and/or hypoxia, (4) PH due to chronic thrombotic and/or embolic disease, (5) PH of other origin (e.g. sarcoidosis). Group (1) is comprising e.g. idiopathic and familial PAH as well as PAH in the context of connective tissue disease (e.g. scleroderma, CREST), congenital systemic to pulmonary shunts, portal hypertension, HIV, intake of drugs and toxins (e.g. anorexigens). PH occurring in COPD was assigned to group (3). Muscularization of small (less than 500 μm diameter) pulmonary arterioles is widely accepted as a common pathological denominator of PAH (Group 1), however it may also occur in other forms of PH such as based on COPD or thrombotic and/or thrombembolic disease. Other pathoanatomical features in PH are thickening of the intima based on migration and proliferation of (myo)fibroblasts or smooth muscle cells and excessive generation of extracellular matrix, endothelial injury and/or proliferation and perivascular inflammatory cell infiltrates. Together, remodelling of distal pulmonary arterial vasculature results in augmented pulmonary vascular resistance, consecutive right heart failure and death. Whilst background therapy and more general measures such as oral anticoagulants, diuretics, digoxin or oxygen supply are still listed by current guidelines these remedies are not expected to interfere with causes or mechanisms of pulmonary arterial remodelling. Some patients with PAH may also benefit from Ca++-antagonists in particular those with acute response to vasodilators. Innovative therapeutic approaches developed over the past decade considered molecular aberrations in particular enhanced endothelin-1 formation, reduced prostacyclin (PGI2) generation and impaired eNOS activity in PAH vasculature. Endothelin-1 acting via ETA-receptors is mitogenic for pulmonary arterial smooth muscle cells and triggers acute vasoconstriction. The oral ETA/ETB-antagonist Bosentan has recently been approved in the EU and United States for treatment of PAH after the compound demonstrated improvements in clinical endpoints such as mean PAP, PVR or 6 min walking test. However, Bosentan augmented liver enzymes and regular liver tests are mandatory. Currently selective ETA antagonists such as sitaxsentan or ambrisentan are under scrutiny.
As another strategy in management of PAH replacement of deficient prostacyclin by PGI2 analogues such as epoprostenol, treprostinil, oral beraprost or iloprost emerged. Prostacyclin serves as a brake to excessive mitogenesis of vascular smooth muscle cells acting to augment cAMP generation. Intravenous prostacyclin (epoprostenol) significantly improved survival rates in idiopathic pulmonary hypertension as well as exercise capacity and was approved in North America and some European countries in the mid-1990s. However, owing to its short half-life epoprostenol has to be administered via continuous intravenous infusion that—whilst feasible—is uncomfortable, complicate and expensive. In addition, adverse events due to systemic effects of prostacyclin are frequent. Alternative prostacyclin analogues are treprostinil, recently approved in the United States for PAH treatment and delivered via continuous subcutaneous infusion and beraprost, the first biologically stable and orally active PGI2 analogue, which has been approved for treatment of PAH in Japan. Its therapeutic profile appeared more favourable in patients with idiopathic PAH compared to other forms of pulmonary hypertension and side effects linked to systemic vasodilation following beraprost administration and local pain at the infusion site under treprostinil treatment are frequent. Administration of the prostacyclin analogue iloprost via the inhalative route was recently approved in Europe. Its beneficial effects on exercise capacity and haemodynamic parameters are to be balanced to a rather high dosing frequency comprising 6-12 courses of inhalation per day from appropriate devices.
Functional consequences of impaired endothelial nitric oxide formation as reported in pulmonary arterial hypertension may be overcome by selective inhibitors of phosphodiesterase-5 (PDE5) that is expressed in pulmonary artery smooth muscle cells. Consequently, the selective PDE5 inhibitor sildenafil was demonstrated to improve pulmonary haemodynamics and exercise capacity in PAH.
Most of these novel treatments primarily address smooth muscle cells function, however, in addition pulmonary vascular fibroblasts, endothelial cells but also perivascular macrophages and T-lymphocytes are considered to contribute to the development of pulmonary hypertension.
In spite of the different therapeutic approaches mentioned above the medical need to alleviate the disease burden in pulmonary hypertension is high. It is therefore an object of the present invention to make available pharmaceutical compositions for the preventive or curative treatment of pulmonary hypertension, which overcome some or all of the abovementioned disadvantages.